ReCardioids: a robust human heart organoid platform to model doxorubicin- and radiotherapy-induced cardiotoxicity

Abstract

As global cancer incidence rises, so does the population of cancer survivors, making long-term and post-treatment quality of life a central clinical concern. Despite modern improvements in treatment, cardiotoxic side effects caused by anthracycline agents and thoracic radiotherapy remain a major clinical challenge. Human iPSC-derived heart organoids offer a promising alternative to animal and 2D in vitro models, but their utility is limited by inter-organoid variability. To address this, we developed reCardioids, a robust heart organoid model generated by dissociation and reaggregation of self-assembling cardioids. Through single-cell transcriptomics, we demonstrated that reCardiods maintain cellular diversity while also exhibiting a more mature cardiomyocyte phenotype compared to non-dissociated cardioids. To validate their utility as a preclinical in vitro model, we evaluated their response after exposure to doxorubicin and clinically relevant doses of {gamma}-radiation. reCardioids successfully modeled doxorubicin-induced cytotoxicity, metabolic decline and altered contractile dynamics. Bulk RNA sequencing following radiation exposure revealed a temporal trajectory of injury, progressing from acute DNA damage through vascular stunting, metabolic dysfunction and eventually compensatory pathological hypertrophic remodeling.